Dataset Information

Progesterone receptor ligands for the treatment of endometriosis: the mechanisms behind therapeutic success and failure.

ABSTRACT:

Background

Despite intense research, it remains intriguing why hormonal therapies in general and progestins in particular sometimes fail in endometriosis.

Objective and rationale

We review here the action mechanisms of progesterone receptor ligands in endometriosis, identify critical differences between the effects of progestins on normal endometrium and endometriosis and envisage pathways to escape drug resistance and improve the therapeutic response of endometriotic lesions to such treatments.

Search methods

We performed a systematic Pubmed search covering articles published since 1958 about the use of progestins, estro-progestins and selective progesterone receptor modulators, to treat endometriosis and its related symptoms. Two reviewers screened the titles and abstracts to select articles for full-text assessment.

Outcomes

Progesterone receptor signalling leads to down-regulation of estrogen receptors and restrains local estradiol production through interference with aromatase and 17 beta-hydroxysteroid dehydrogenase type 1. Progestins inhibit cell proliferation, inflammation, neovascularisation and neurogenesis in endometriosis. However, progesterone receptor expression is reduced and disrupted in endometriotic lesions, with predominance of the less active isoform (PRA) over the full-length, active isoform (PRB), due to epigenetic abnormalities affecting the PGR gene transcription. Oxidative stress is another mechanism involved in progesterone resistance in endometriosis. Among the molecular targets of progesterone in the normal endometrium that resist progestin action in endometriotic cells are the nuclear transcription factor FOXO1, matrix metalloproteinases, the transmembrane gap junction protein connexin 43 and paracrine regulators of estradiol metabolism. Compared to other phenotypes, deep endometriosis appears to be more resistant to size regression upon medical treatments. Individual genetic characteristics can affect the bioavailability and pharmacodynamics of hormonal drugs used to treat endometriosis and, hence, explain part of the variability in the therapeutic response.

Wider implications

Medical treatment of endometriosis needs urgent innovation, which should start by deeper understanding of the disease core features and diverse phenotypes and idiosyncrasies, while moving from pure hormonal treatments to drug combinations or novel molecules capable of restoring the various homeostatic mechanisms disrupted by endometriotic lesions.

SUBMITTER: Reis FM

PROVIDER: S-EPMC7317284 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Progesterone receptor ligands for the treatment of endometriosis: the mechanisms behind therapeutic success and failure.

Reis Fernando M FM Coutinho Larissa M LM Vannuccini Silvia S Batteux Frédéric F Chapron Charles C Petraglia Felice F

Human reproduction update 20200601 4

<h4>Background</h4>Despite intense research, it remains intriguing why hormonal therapies in general and progestins in particular sometimes fail in endometriosis.<h4>Objective and rationale</h4>We review here the action mechanisms of progesterone receptor ligands in endometriosis, identify critical differences between the effects of progestins on normal endometrium and endometriosis and envisage pathways to escape drug resistance and improve the therapeutic response of endometriotic lesions to s ...[more]

PMID: 32412587

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Project description:Current medical treatments for endometriosis are very limited. Progestin and selective progesterone receptor modulators (SPRM) are developed but their efficacy, safety, mechanism and recurrence in endometriosis are not fully studied.In order to compare therapeutic, side effects and therapeutic actions of Esmya, Duphaston and Dienogest in endometriosis. Experimental endometriosis was induced by either intraperitoneal or subcutaneous mouse endometrium transplantation. Lesion size, weight and histology at the end of intervention were compared. Expression of related markers in the endometriotic lesions were examined. Body, uterus and ovary weights, endometrial glands and thickness (ETI), and follicle count were measured. For recurrent study, lesion growth before and after intervention was monitored.After Esmya, Duphaston, Dienogest treatment, lesion size and weight were significantly decreased. Proliferation Pcna expression was significantly decreased in all groups, but proliferation cells were significantly decreased only in Duphaston group. Apoptosis Mapk1 expression and TUNEL-positive cells were significantly increased in Duphaston group. Adhesion Mmp2 and Itgav?3 expression were significantly increased in Esmya group. Plau, Hif1? and Vegfa expression, peritoneal fluid PGE2 levels, and ER? and ER? expression were not affected; while PR expression was significantly lower in all groups. Endometrial gland count in uterus was significantly increased in Dienogest group, ETI was significantly decreased in Duphaston group, and AFC were significantly increased in Esmya group. Upon treatment cessation, lesion growth rebound quickly in Dienogest and Duphaston groups, but slowly in Esmya group.Esmya, Duphaston and Dienogest are effective anti-endometriosis drugs targeting proliferation, apoptosis and adhesion. Esmya, Duphaston and Dienogest are all well tolerable, although endometrial glandular hyperplasia was found in Dienogest, endometrial atrophy in Duphaston, follicle accumulation in Esmya.

Project description:Context:Progesterone (P) resistance is a hallmark of endometriosis, but the underlying mechanism(s) for loss of P sensitivity leading to lesion establishment remains poorly understood. Objective:To evaluate the association between Notch-1 signaling activation and P resistance in the progression of endometriosis. Design:Case control study; archived formalin-fixed, paraffin-embedded tissues. Setting:University hospitals (United States, Taiwan). Patients:Women with endometriosis; human endometrial stromal cell line (HESC). Intervention:Eutopic endometria (EU) and ectopic lesions (ECs) were collected from surgically diagnosed patients. Archived tissue sections of EU and ECs were identified. HESCs were treated with N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) and valproic acid (VPA) to, respectively, suppress and induce Notch-1 activation. Outcome Measures:Tissues were analyzed for Notch Intra-Cellular Domain 1 (NICD1) and progesterone receptor (PGR) protein expression by immunohistochemistry and for transcript levels of NICD1 target genes HES1, PGR, and PGR-B by quantitative reverse transcription polymerase chain reaction. DAPT- or VPA-treated HESCs with and without P cotreatment were evaluated for cell numbers and for PGR, HES1, and PGR target gene DKK1 transcript levels. Results:Nuclear-localized stromal NICD1 protein levels were inversely associated with those of total PGR in EU and ECs. Stromal ECs displayed higher HES1 and lower total PGR and PGR-B transcript levels than EU. In HESCs, DAPT reduction of NICD1 decreased cell numbers and increased PGR transcript and nuclear PGR protein levels and, with P cotreatment, maintained P sensitivity. Conversely, VPA induction of NICD1 decreased PGR transcript levels and, with P cotreatment, abrogated P-induced DKK1 and maintained HES1 transcript levels. Conclusions:Aberrant Notch-1 activation is associated with decreased PGR that contributes to P resistance in endometriosis.

Dataset Information

Progesterone receptor ligands for the treatment of endometriosis: the mechanisms behind therapeutic success and failure.

Background

Objective and rationale

Search methods

Outcomes

Wider implications

Publications

Progesterone receptor ligands for the treatment of endometriosis: the mechanisms behind therapeutic success and failure.

Similar Datasets

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